DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus.
DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus.
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DOI：
10.1186/gb-2013-14-5-r50
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发表时间：
2013-05-28
期刊：
影响因子：
12.3
通讯作者：
Ketting RF
中科院分区：
文献类型：
--
作者：
Kaaij LT;van de Wetering M;Fang F;Decato B;Molaro A;van de Werken HJ;van Es JH;Schuijers J;de Wit E;de Laat W;Hannon GJ;Clevers HC;Smith AD;Ketting RF
DNA甲基化在发育过程中起着至关重要的作用。以前的全基因组研究确定了干细胞分化后的许多差异甲基化区域，其中许多与转录起始位点相关。我们提出了第一个全基因组，单碱基分辨率的观点，在哺乳动物上皮干细胞分化过程中的DNA甲基化动力学：小鼠小肠LGR 5+干细胞。在转录起始位点观察到很少的变化，我们的数据表明分化相关基因已经在干细胞中表达。全基因组范围内，只有50个差异甲基化区域被确定。几乎所有这些基因座都代表了在小肠的分化部分中驱动基因表达的增强子。最后，我们表明，转录因子Tcf4的结合与低甲基化相关，并证明Tcf4是形成差异甲基化区域的因素之一。我们的研究结果揭示了小肠干细胞分化过程中有限的DNA甲基化动力学，以及转录因子结合对体内干细胞分化过程中DNA甲基化景观的影响。
DNA methylation is of pivotal importance during development. Previous genome-wide studies identified numerous differentially methylated regions upon differentiation of stem cells, many of them associated with transcriptional start sites. We present the first genome-wide, single-base-resolution view into DNA methylation dynamics during differentiation of a mammalian epithelial stem cell: the mouse small intestinal Lgr5+ stem cell. Very little change was observed at transcriptional start sites and our data suggest that differentiation-related genes are already primed for expression in the stem cell. Genome-wide, only 50 differentially methylated regions were identified. Almost all of these loci represent enhancers driving gene expression in the differentiated part of the small intestine. Finally, we show that binding of the transcription factor Tcf4 correlates with hypo-methylation and demonstrate that Tcf4 is one of the factors contributing to formation of differentially methylated regions. Our results reveal limited DNA methylation dynamics during small intestine stem cell differentiation and an impact of transcription factor binding on shaping the DNA methylation landscape during differentiation of stem cells in vivo.
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